CH624105A5 - Process for the preparation of novel azatetracyclic compounds - Google Patents

Description

The present invention relates to a process for the preparation of new azatetracycles and their acid addition salts with valuable pharmacological properties.

Polycyclic compounds with such properties are already known, e.g. from US-PS 3 636 045.3 636 046, 3 749 790, 3 786 045.3 682 959.3 798 237.3 777 032, 3 772 348,

3 783 161, 3 726 897, 3 773 940.3 755 357.3 859 439, 3 996 373,

4 002 632, BE-PS 835 523 and DT-OS 2 509 617.

The azatetracycles obtainable according to the invention correspond to the formula

R,

Nv

(I)

S \ '\

I A II II II

• • - • •

V V

in which

Rj is hydrogen, lower alkyl, cycloalkyl-lower alkyl having up to 10 carbon atoms, lower alkenyl, lower alkynyl, di-lower-alkylamino-lower alkyl, free, etherified or esterified hydroxy-lower alkyl, etherified mercapto-lower alkyl, or optionally substituted phenyl-lower alkyl, an optionally present hetero atom being separated from the ring nitrogen atom by at least 2 carbon atoms , and the ring A is unsubstituted or substituted by halogen to atom number 35, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl or cyano,

X oxygen, sulfur, methylene or a divalent radical of the sub-formula

\ /

N

I.

r3

fla)

means in which R3 represents hydrogen or lower alkyl, and one of the radicals

Y and Z means vinylene or sulfur and the other means a direct bond.

The invention also relates to a process for the preparation of the acid addition salts of the compounds of the formula I, in particular the pharmaceutically acceptable acid addition salts.

5 In the above definition of formula I and below, lower radicals are understood to mean those having at most 8 and preferably at most 4 carbon atoms.

Rj preferably contains 1 to 6 carbon atoms as lower alkyl. These lower alkyl groups, which can be straight-chain or branched, are e.g. Methyl, ethyl, propyl, iso-propyl, butyl, isobutyl or tertiary butyl.

The radical Rj preferably contains 4 to 8 carbon atoms as cycloalkyl-lower alkyl. Cycloalkyl-lower alkyl is e.g. Cyclopropylmethyl, cyclobutylmethyl and especially i5 cyclopentylmethyl, cyclohexylmethyl, further e.g. Cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl.

The radical Rj preferably contains 3 to 4 carbon atoms and in particular 3 carbon atoms as lower alkenyl. Niederalkenyl is e.g. as allyl or 2-methylallyl. 20 As lower alkynyl, the Rx radical is in particular propargyl.

In diniederalkylamino lower alkyl as the radical Ra, the nitrogen atom is separated from the ring nitrogen atom by at least 2 carbon atoms. This radical preferably contains up to 10 carbon atoms, in particular 4-6 carbon-25 atoms. The lower alkyl residues in this substituent are preferably straight-chain. All the rest is e.g. Diethylamino - butyl, propyl or ethyl, dimethylamino butyl, ethyl and especially dimethylamino propyl.

In the hydroxy lower alkyl radical Rj, the hydroxyl group 30 is separated from the ring nitrogen atom by at least 2 carbon atoms. This radical contains 2 to 8 and preferably 2 to 6 carbon atoms. The hydroxy lower alkyl, which may be straight chain or branched, is e.g. l-methyl-2-hydroxyethyl, 2- or 3-hydroxypropyl, 1- or 2-methyl-2-hydroxy-35 propyl, and especially 2-hydroxyethyl.

In lower alkoxy lower alkyl as the Rt radical, the oxygen atom is separated from the ring nitrogen atom by at least 2 carbon atoms. This rest contains e.g. 3 to 10 and preferably 3 to 6 carbon atoms. This lower alkoxy lower-40 alkyl is e.g. the 2- or 3-methoxypropyl, 2- or 3-ethoxypropyl, 2- or 3-propoxypropyl, 3-isopropoxypropyl and in particular the 2-methoxy or 2-ethoxyethyl.

In the alkanoyloxy lower alkyl radical Rj, the oxygen atom is separated from the ring nitrogen atom by at least 2 carbon atoms. This rest contains e.g. 3 to 10 and preferably 3 to 7 carbon atoms. This rest is e.g. 2-Formyloxy-ethyl, 2-acetyloxy-ethyl, 2-propionyloxy-ethyl, 2- or 3-acetyloxypropyl, 2-methyl-3-acetyloxypropyl or 2- or 3-propionyloxypropyl.

so in lower alkylthio-lower alkyl as the radical Ra the sulfur atom is separated from the ring nitrogen atom by at least 2 carbon atoms. This rest contains e.g. 3 to 10 and preferably 3 to 6 carbon atoms. This lower alkylthio lower alkyl is especially 2-methylthio or 2-ethyl-55 thioethyl.

Rj contains, as optionally substituted phenyl-lower alkyl in the phenyl ring, for example halogen to atom number 35, lower alkyl and lower alkoxy, methylenedioxy and trifluoromethyl, in particular chlorine, methyl or methoxy. 60 Ring A can be mono- or polysubstituted. However, it is preferably monosubstituted by halogen to atom number 35, especially chlorine, lower alkyl with at most 4 carbon atoms, such as ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and especially methyl, lower alkoxy with 65 at most 4 carbon atoms, such as ethoxy, propoxy, Iso-propoxy, butoxy, isobutoxy and especially methoxy, lower alkylthio with at most 4 carbon atoms, such as ethylthio, propylthio, isopropylthio, butylthio, isopropylthio, butylthio

624105

and especially methylthio, as well as by trifluoromethyl or cyan.

If X is the divalent remainder of sub-formula Ia

\ /

N

I there)

r3

R3 is preferably hydrogen or lower alkyl with at most 4 carbon atoms, such as propyl, butyl, isobutyl and especially methyl or ethyl.

Y is preferably a direct bond and Z is vinylene or sulfur.

Salts of compounds of formula I are primarily acid addition salts, especially pharmaceutically acceptable acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids, such as organic carboxylic and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, fumaric acid Maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid or embonic acid.

The new azatetracycles of general formula I and their acid addition salts have valuable pharmacological, e.g. properties acting on the central nervous system. They are primarily characterized by central depressant, anti-agitation (amphetamine-antagonistic) effects, which can be demonstrated by pharmacological tests. They show in the rat in the amphetamine antagonism test [Niemegeers and Janssen, Arzneimittelforsch., Vol. 24, p. 45 (1974)] in a dose range of 0.5 to 50 mg / kg i.p. an anti-arousal effect. The cataleptic effect is relatively low compared to the amphetamine-antagonistic effect. The new azatetracycles of the general formula I and their pharmaceutically acceptable acid addition salts can therefore be used as tranquilizing, antipsychotic and anti-irritating compounds for the treatment of arousal states.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Rx is hydrogen, lower alkyl, cycloalkyl-lower alkyl having up to 10 carbon atoms, lower alkenyl, lower alkynyl, di-lower alkyl-amino lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, alkanoyloxy-lower alkyl, lower alkylthio-lower alkyl, or phenyl-lower alkyl, and ring A is unsubstituted or substituted by halogen to atom number 35, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl or cyano, X is oxygen, sulfur, methylene or the divalent radical of sub-formula Ia

\ /

N

R-î

(Ia)

means in which R3 represents hydrogen or lower alkyl, and one of the radicals Y and Z is vinylene or sulfur and the other means a direct bond, and salts, in particular acid addition salts, primarily pharmaceutically acceptable acid addition salts thereof.

The invention relates primarily to a process for the preparation of compounds of formula I wherein Rx is hydrogen, lower alkyl, e.g. Methyl or ethyl, cycloalkyl-lower alkyl of 4-8 carbon atoms, e.g. Cyclopentylmethyl and cyclohexylmethyl, lower alkenyl, e.g. Allyl, lower alkynyl, e.g. Propargyl, di-lower alkylamino lower alkyl, e.g. Di-

methylaminoethyl and 3-dimethylaminopropyl, hydroxy lower alkyl, e.g. 2-hydroxyethyl and 3-hydroxypropyl, lower alkoxy lower alkyl, e.g. 3-methoxy and 3-ethoxypropyl, lower alkylthio lower alkyl, e.g. 2-methylthio and 2-ethylthio-5 ethyl, 3-methylthio and 3-ethylthio-propyl or phenyl-lower alkyl, e.g. Benzyl means that the ring A is unsubstituted or substituted by halogen to atom number 35, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl or cyano, X means oxygen, sulfur, methylene or the divalent • io radical of sub-formula Ia,

\ /

N

I.

Ra

(Ia)

in which R3 is hydrogen or lower alkyl, preferably methyl or ethyl and one of the radicals Y and Z is vinylene or sulfur and the other is a direct bond, 20 and salts, in particular acid addition salts, primarily pharmaceutically acceptable acid addition salts thereof.

The invention particularly relates to a process for the preparation of compounds of formula I wherein Rj is hydrogen, lower alkyl, e.g. Methyl or ethyl, cycloalkylnie-25 deralkyl having 4-8 carbon atoms, e.g. Cyclopentylmethyl and cyclohexylmethyl, lower alkenyl, e.g. Allyl, lower alkynyl, e.g. Propargyl, di-lower alkylamino lower alkyl, e.g. Dimethylaminoethyl and 3-dimethylaminopropyl, hydroxy lower alkyl, e.g. 2-hydroxyethyl and 3-hydroxypropyl, never-30 deralkoxy-lower alkyl, e.g. 3-methoxy and 3-ethoxypropyl, lower alkylthio lower alkyl, e.g. 2-methylthio and 2-ethylthio-ethyl, 3-methylthio and 3-ethylthio-propyl, or phenyl-lower alkyl, e.g. Benzyl means that ring A is unsubstituted or substituted by chlorine, X is sulfur or methylene 35 and Y is a direct bond and Z is vinylene or sulfur, and salts, especially acid addition salts, primarily pharmaceutically acceptable acid addition salts thereof.

The invention relates in particular to a process for the preparation of compounds of the formula I in which R 1 is hydrogen or lower alkyl, e.g. Methyl or ethyl and the ring A is unsubstituted, X is sulfur or methylene and Y is a direct bond and Z is vinylene or sulfur, such as 3-methyl-2,3,4,5-tetrahydro-lH-dibenzo [2 3 ' .6,7] -45 thiepino [4,5-a] azepine and salts thereof, especially acid addition salts, primarily pharmaceutically acceptable acid addition salts thereof.

The compounds of formula I are prepared according to the invention by using a reactive diester of such a diethanois of the formula

HIGH,

CH2 - 0H

(Ii)

X

with a compound of formula t

N

/ \

H H

implements.

(III)

5

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As reactive diesters of a diet hanoi of formula II, esters of strong inorganic acids such as e.g. Hydrofluoric acid, bis-iodohydrate or in particular bis-hydrobromate or hydrogen bromide-hydrochloric acid are used. Corresponding diesters of organic acids, e.g. of sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, p-chloro- or p-bromo-benzenesulfonic acid or p-toluenesulfonic acid, can be used. These diesters of the compounds of formula II are preferably reacted in a suitable inert solvent at a reaction temperature of 20 to 130 ° C. Suitable inert solvents are, for example, hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as chloroform, lower alcohols such as ethanol and especially methanol, ethereal liquids such as ether or dioxane, and lower alkanones, e.g. Acetone, methyl ethyl ketone or diethyl ketone or mixtures of such solvents, e.g. Benzene-methanol.

In the reaction according to the invention of one molar equivalent of diester of a diethanois of the formula II with one molar equivalent of free base of the formula III, two molar equivalents of acid are split off, which are preferably bound to an acid-binding agent. Suitable acid-binding agents are e.g. Alkali carbonates such as potassium carbonate or e.g. Alkali hydroxides, such as sodium hydroxide or potassium hydroxide, or excess base of formula III, furthermore tertiary organic bases, such as pyridine and in particular triethylamine or N-ethyl-diisopropylamine.

The immediate starting materials, that is to say the reactive diesters of the formula II, can be prepared from the corresponding diethanols by esterification or replacement of the hydroxy groups by halogen by customary methods. The diethan in turn can be prepared from the corresponding methyl diacetates by reduction with lithium aluminum hydride. The methyl diesters can be prepared from the corresponding diacetonitriles with methanol and 2 molar equivalents of water with the introduction of hydrogen chloride. The diacetonitriles in turn can be obtained from the corresponding bis (bromomethyl) compounds with sodium cyanide.

Following the reactions according to the invention, a series of conversions can optionally be carried out which convert compounds of the formula I into other compounds of the formula I.

If appropriate, a compound of the formula I whose radical Rj is hydrogen can be converted into a process product whose radical Rx has one of the other meanings.

For example, N substitution is carried out either with a reactive ester of a corresponding alcohol of the formula R ^ v - OH, in which RXIV has the same meaning as Rx in formula I, with the exception of hydrogen, or by reaction with corresponding aldehydes or ketones with reducing agents Conditions.

The reaction of compounds of the formula I in which Rx is hydrogen with a reactive ester of a hydroxy compound of the formula RIV-OH is preferably carried out in a solvent at a reaction temperature of 20 to 130 ° C., in particular at the boiling point of the solvent.

As reactive esters e.g. Halides, such as chlorides or bromides, also sulfonic acid esters, such as the o- or p-toluenesulfonic acid methyl ester or ethyl ester, or sulfuric acid esters, e.g. the dimethyl or diethyl sulfate can be used. Al-potassium carbonates are suitable as acid-binding agents, e.g. Potassium carbonate, or alkali hydroxides, e.g. Sodium hydroxide, or tertiary organic bases such as e.g. Pyridine or the N-ethyldiisopropylamine. Suitable solvents are those solvents which are inert under the reaction conditions, for example hydrocarbons such as benzene or toluene, and also alkanols such as e.g. Methanol or ethanol, or alkanones such as acetone or methyl ethyl ketone.

Aldehydes and ketones which correspond to the alcohols of the formula R: IV - OH are e.g. lower aliphatic aldehydes or ketones, lower free, esterified or etherified hydroxyoxyalkanes or esterified oxoalkane carboxylic acids. The reaction product obtained in the reaction of these aldehydes or ketones with the compounds of the formula I mentioned can be reduced in the same operation or subsequently.

The aldehydes, e.g. Formaldehyde or acetaldehyde, or the ketones, e.g. Acetone, for example, are warmed to about 30 ° to 100 ° C. with the compounds of the formula I mentioned in an inert solvent, and at the same time or subsequently the reaction mixture is hydrogenated with hydrogen in the presence of a catalyst. Suitable solvents are e.g. Alkanols, such as methanol or ethanol, and suitable catalysts. Precious metal catalysts, such as palladium on carbon, or alloy skeleton catalysts, such as Raney nickel.

Instead of hydrogen in the presence of a catalyst, other reducing agents, e.g. Formic acid, used for reductive alkylation. According to this variant of the process, the compounds of the formula I are heated with formic acid and the types of aldehydes or ketones, in particular formaldehyde, preferably without solvent.

Furthermore, a compound of formula I, the radical Rt of which is a hydroxy-lower alkyl group, can optionally be acylated to a compound whose radical Rj is an esterified hydroxy-lower alkyl group.

Acylation can e.g. with a carboxylic acid anhydride or with an appropriate carbonyl halide at a reaction temperature between about 20 and 100 ° C. Since the condensation takes place with the elimination of acid, it is expedient to add an acid-binding agent, e.g. add a tertiary organic base such as pyridine. Excess tertiary organic base can also be used as a solvent. Furthermore, hydrocarbons, e.g. Benzene or toluene, or halogenated hydrocarbons, e.g. Chloroform.

Furthermore, a compound of formula I, the radical Rj of which is a phenyl-lower alkyl group, can optionally be hydrogenolyzed to a process product, the radical Rx of which is hydrogen.

The hydrogenolysis can be carried out using conventional hydrogenation catalysts, for example noble metal catalysts such as palladium on carbon or platinum oxide, rhodium catalysts such as rhodium on carbon or on aluminum oxide, or alloy skeleton catalysts such as Raney nickel, in an inert organic solvent such as methanol, ethanol or Dioxane, at room temperature and normal pressure or moderately elevated temperatures up to about 100 ° C and / or elevated pressures up to about 100 bar.

Furthermore, a compound of the formula I, in which X is a divalent radical of the sub-formula, may optionally be used

\ /

N

I (Ia)

Ra means, and where R3 represents hydrogen, into another

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Process product are transferred, the rest of which R3 represents lower alkyl.

This conversion is preferably carried out by reacting the abovementioned process product with a reactive lower alkyl ester in the presence of solvents and basic condensing agents.

As reactive esters e.g. Halides, such as chlorides or bromides, also sulfonic acid esters, such as the o- or p-toluenesulfonic acid methyl ester or ethyl ester, or sulfuric acid esters, e.g. the dimethyl or diethyl sulfate can be used. Suitable basic condensing agents are alkali metal alkanolates, such as potassium tert-butoxide, or corresponding amides, such as sodium amide, or metal hydrides, such as sodium or lithium hydride. Suitable solvents are those solvents which are inert under the reaction conditions, for example hydrocarbons such as benzene or toluene, and also ether-like liquids, e.g. Tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, or amides, such as phosphoric acid hexamethyl triamide or dimethylformamide.

Furthermore, a compound of the formula I, in which X is a divalent radical of the sub-formula, can optionally be used

\ /

N

I (Ia) -

Rs means, and wherein R3 represents lower alkanoyl or lower alkoxy-carbonyl, are reduced to a process product, the rest of which R3 represents lower alkyl. This reduction is preferably carried out using a hydride. Diborane is preferably used as the hydride in an ethereal reaction medium, such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether. The reaction temperature is, for example, from −20 ° C. to + 80 ° C., preferably between 0 ° C. and room temperature. The required diborane is, for example, either separately from boron trifluoride etherate and sodium borohydride, e.g. in the solvent used for the reduction, formed and used as a solution, or formed, for example, in diethylene glycol dimethyl ether and introduced as a gas into the reaction mixture, or formed in situ.

Depending on the process conditions and starting materials, the end products are optionally obtained in free form or in the form of their salts, which can be converted into one another or into other salts in the customary manner. Thus free compounds of formula I are formed from acid addition salts obtained, e.g. by treatment with bases or basic ion exchangers, while free bases of formula I e.g. converted into acid addition salts by reaction with organic or inorganic acids, in particular those which are suitable for the formation of pharmaceutically usable salts, such as the abovementioned.

Salts of the new compounds can also be used for cleaning purposes, e.g. by converting the free compounds into their salts, isolating them and, if necessary, purifying them, and converting them back into the free compounds. As a result of the close relationships between the new compounds in free form and in the form of their salts, in the preceding and the following, the free compounds are also to be understood as meaningful and expedient, if appropriate, the corresponding salts.

Appropriately, for the implementation of the process according to the invention, those starting materials are used which lead to the groups of end products which were particularly mentioned at the beginning and in particular to the end products which have been specifically described or highlighted.

The new connections can e.g. in the form of pharmaceutical preparations which contain an effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral, e.g. oral, or parenteral administration are suitable. Thus, tablets or gelatin capsules are used which contain the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Have silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colors, flavors and sweeteners. Furthermore, the new pharmacologically active compounds can be administered in the form of injectable, e.g. Use intravenous, administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these being e.g. from lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. Mannitol can be prepared before use. The pharmaceutical preparations can be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are manufactured in a manner known per se, e.g. by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing processes, and contains from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient. Dosage depends on the mode of application, the species, the age and the individual condition. Daily doses of the free bases or pharmaceutically acceptable salts thereof range from about 0.01 g to about 1.0 g for warm-blooded animals weighing about 70 kg.

The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius.

example 1

To a solution of 21.8 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenzo [a, d] cycloheptene in 200 ml of absolute ethanol is added 35 ml (2.6 g; 0.06 mol) of a 7.4% ethanolic ethylamine solution and 15.5 g (0.125 mol) diisopropylethylamine and the reaction mixture is refluxed for 18 hours. The reaction mixture is then concentrated in a water jet vacuum, the residue is dissolved in 300 ml of methylene chloride and this solution is washed successively with 100 ml of 2-n. Caustic soda and water. The methylene chloride solution is concentrated in a water jet vacuum to approx. 50 ml and with 15 ml 4-n. ethereal hydrogen chloride solution, the 3-ethyl-l, 2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [l, 2-d] azepine hydrochloride of mp. Crystallized 296-299 °.

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Mp of methanesulfonate: 220-221 °.

The starting material can be prepared in the following manner, namely analogously to the information in Example 5: from 27 g (0.1 mol) of 5H-dibenzo [a, d] cycloheptene-10, l 1-di-acetonitrile, 400 ml of methanol , 3.8 ml of water and dry hydrogen chloride the 5H-dibenzo [a, d] cyclohepten-10, l 1-di-acetic acid dimethyl ester, mp. 104-106 ° (from hexane);

5H-Diben from 33.6 g (0.1 mol) of 5H-dibenzo [a, d] cyclohepten-10, 1 l of 1-di-acetic acid dimethyl ester and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether -zo [a, d] cyclohepten-10, ll-diethanol, mp. 154-156 ° (from acetone).

To a solution of 28.0 g (0.10 mol 5H-dibenzo [a, d] -cyclohepten-10,11-diethanol in 120 ml pyridine is added dropwise at a reaction temperature of -5 ° 16.8 ml (25.2 g; 0.22 mol) of methanesulfonic acid chloride, followed by stirring for 30 minutes at 0 ° and then for one hour at 15-25 ° C. The reaction mixture is mixed with 600 ml of methylene chloride in a separating funnel in succession with 400 ml of 5N hydrochloric acid each The methylene chloride solution is separated off, dried over magnesium sulfate and evaporated in a water jet vacuum, leaving 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -5H-diben-zo [a, d] cycloheptene as the residue colorless viscous oil.

The following can be prepared in an analogous manner: 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclo-hepta [1,2-d] azepine methanesulfonate, mp . 189-191 °, starting from 21.8 g (0.05 mol) of 10.11 -Bis- [2- (methyisulfonyloxy) - ethyl] - 5H-dibenzo [a, d] cycloheptane, 30 ml (1, 9 g; 0.06 mol) of a 6.3% ethanolic methylamine solution and 15.5 g (0.125 mol) diisopropylethylamine.

3-benzyl-12,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclo-hepta [l, 2-d] azepine hydrochloride, mp. 265-270 °, starting from 21 , 8 g (0.05 mol) 10, 11-bis- [2- (methylsulfonyloxy) ethyl] - 5H-dibenzo [a, d] cycloheptene, 6.2 g (0.06 mol) benzylamine and 15, 5 g (0.125 mol) of diisopropylethylamine.

Example 2

A suspension of 19.4 g (0.05 mol) of 3-benzyl-l, 2,3,4,5, -10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [l, 2-d] azepine hydrochloride and 2 g of 5% Pd carbon in 900 ml of methanol is hydrogenated at normal pressure and 40-50 ° until 770 ml of hydrogen are taken up. The catalyst is then filtered off and the filtrate is evaporated in a water jet vacuum.

The crude 1,2,3,4,5,10-He-xahydro-dibenzo [3,4; 6,7] cyclohepta [1,2-d] azepine hydrochloride which remains as a residue is recrystallized from ethanol, mp 295 -300 °.

To release the base, the hydrochloride is suspended in 250 ml of methylene chloride and concentrated with 100 ml. Ammonia solution shaken. The methylene chloride solution is separated off and concentrated until crystallization begins.

Then hexane is added, the 1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine, mp. 190 to 191 ° crystallized out.

For conversion to methanesulfonate, the free base is dissolved in methylene chloride, the theoretical amount of methanesulfonic acid is added, and the 1,2,3,4,5,10-hexahydro-dibenzo-

[3,4: 6,7] cyclohepta [1,2-d] azepine methanesulfonate precipitated with ether, mp. 269-271 °.

Example 3

11 are added to a solution of 43.6 g (0.1 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenzo [a, d] cycloheptane in 400 ml of absolute ethanol , 9 g (0.12 mol) of (aminomethyl) cyclopentane and 32.3 g (0.25 mol) of diisopropylethylamine and the reaction mixture is refluxed for 20 hours. The reaction mixture is then concentrated in a water jet vacuum, the residue is dissolved in 150 ml of methylene chloride and 500 ml of pentane and this solution is washed successively with 200 ml of 2-n. Caustic soda and water. The organic phase is then mixed with 200 ml of 2-n. Hydrochloric acid, whereby the hydrochloride is deposited in granular form. The crystals are filtered off with suction and to release the base, the hydrochloride is suspended in 300 ml of methylene chloride and concentrated with 100 ml. Ammonia solution shaken. The methylene chloride solution is separated off and concentrated until crystallization begins. Then hexane is added, the 3- (cyclopentylmethyl) -1,2,3,4,5,10-hexahydro-dibenzo [3,4: -6,7] cyclohepta [1,2-d] azepine of mp 141-142 ° crystallized. For conversion into methanesulfonate, the base is dissolved in methylene chloride, the theoretical amount of methanesulfonic acid is added, and the 3- (cyclopentylmethyl) -1,2,3,4,5, -10-hexahydro-dibenzo [3,4: 6, 7] cyclohepta [l, 2-d] azepine-methanesulfonate precipitated with ether, mp. 248-249 °.

Example 4

26.1 g (0.1 mol) of 1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] -cyclohepta [1,2-d] azepine (prepared according to Example 2) 92 g (2 mol) of formic acid and 20 g (0.2 mol) of 30% formaldehyde are added while cooling with ice and the mixture is stirred at 95 to 100 ° for 1 hour. Then it is poured onto ice-water and with 10-n. Sodium hydroxide solution made alkaline. The precipitated base is taken up in methylene chloride and the methylene chloride solution is concentrated until crystallization begins. Then hexane is added, the 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d] aze-pin of mp 144-146 ° crystallized. For conversion into methanesulfonate, the base is dissolved in methylene chloride, the theoretical amount of methanesulfonic acid is added and the 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta- [ 1,2-d] azepine methanesulfonate precipitated with ether, mp. 189 to 191 °.

Example 5

To a solution of 4.56 g (0.01 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin in 50 ml of absolute ethanol is added 1.3 g (0.012 mol) of benzylamine and 3.25 g (0.025 mol) of diisopropylethylamine and the reaction mixture is refluxed for 18 hours. After cooling with an ice bath, crystals separate out, which are suction filtered and washed with a little isopropanol and pentane. The suction filter is 3-benzyl-1,2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, mp. 149-150 ° .

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For conversion into the hydrochloride, 3.0 g of the base are dissolved in 100 ml of acetone and 2.2 ml of a 4-n are added with stirring. Hydrogen chloride solution in ether and add enough ether until the solution becomes slightly cloudy. The 3-benzyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine hydrochloride is allowed to crystallize, mp 241-242 ° .

The starting material can be produced in the following way:

58 g (0.2 mol) of dibenzo [b, f] thiepin-10, l of 1-diacetonitiil are suspended in 800 ml of methanol and 7.5 ml of water with stirring and cooled to 0-5 ° in an ice bath. Dry hydrogen chloride is then passed in for 1 hour, a clear solution being formed. The temperature should be kept at 5-20 ° during the introduction. The reaction mixture is then stirred for 1 hour at room temperature, then for 4 hours while refluxing and then completely evaporated on a rotary evaporator. The residue is dissolved in ether, the ether solution is washed with water and 2-n. Soda solution and evaporate completely after drying over sodium sulfate. The oily residue is dissolved in methanol and cooled to 0 °, whereupon the dibenzo [b, f] thiepin-10,11-diacetic acid methyl ester crystallizes, which, after suction filtration and drying at 50 ° under reduced pressure, at 84 -86 ° melts.

A solution of 35.4 g (0.1 mol) of dibenzo is added to a suspension of 7.6 g (0.2 mol) of lithium aluminum hydride in 400 ml of absolute diethyl ether with stirring and exclusion of moisture and in a nitrogen atmosphere within 1 hour. f] thiepin-10, l of dimethyl 1-diacetate in 1 liter of absolute diethyl ether and then boiling the reaction mixture at reflux for 16 hours. After cooling to 0-5 °, the reaction mixture is added dropwise with 130 ml of water and then the organic phase is separated off; they are washed with water and, after drying over sodium sulfate, evaporated to a small volume, the dibenzo [b, f] thiepin-10, l 1-diethanol of mp 131-133 ° crystallizing out.

15 g (0.05 mol) of dibenzo [b, f] thiepin-10, l 1-diethanol are dissolved in 60 ml of pyridine at room temperature and added dropwise with 8.4 in an ice-sodium chloride bath at a reaction temperature of -5 ° ml (12.6 g; 0.11 mol) of methanesulfonic acid chloride were added. The reaction mixture is then stirred at 0 ° for 30 minutes and then at 15-25 ° for 1 hour. Then it is mixed with 500 ml of methylene chloride in a separating funnel in succession with 400 ml of 2-n. Hydrochloric acid and water shaken out. The methylene chloride solution is separated off, dried over magnesium sulfate and evaporated in a water jet vacuum. The 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo- [b, f] thiepin of mp 107-108 ° remains as residue.

Example 6

Analogously to Example 5, the following compounds can be prepared using the corresponding starting materials:

A) from 22.7 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin, 7.3 g (0.06 mol) 2 -Phenylethylamine and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol, the 3- (2-phenylethyl) -2,3,4,5-tetrahydro-lH - dibenzo [2,3: 6 , 7] thiepino [4,5-d] azepine, mp 96-99 ° (from acetonitrile); Methanesulfonate mp 161-164 ° (from absolute ethanol);

B) from 24.2 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -2-methoxydibenzo [b, f] thiepin, 1.85 g of methylamine (0 , 06 mol) and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol, the 7-methoxy-3-methyl-2,3,4,5-tetrahy-dro-1H-dibenzo [23: 6.7] thiepino [4,5-d] azepine, m.p. 108-112 ° (from acetone); Hydrochloride mp 220-224 ° (from absolute ethanol);

C) from 25.0 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -2-methylthio-dibenzo [b, f] thiepin, 6.0 g (0, 06 mol) (aminomethyl) cyclopentane and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol the 7-methylthio-3- (cy-clopentylmethyl) -2,3,4,5-tetrahydro-lH-dibenzo [ 2,3: 6,7] thie-pino [4,5-d] azepine, crude product; Methanesulfonate mp 206 to 209 ° (from absolute ethanol);

D) from 23.4 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -2-methyldibenzo [b, f] thiepin, 1.85 g (0, 06 mol) methylamine and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol the 3,7-dimethyl-2,3,4,5-tetrahydro-lH-di-benzo [2,3: 6,7] thiepino [4,5-d] azepine, crude product; Hydrochloride mp 265-268 ° (from absolute ethanol);

E) from 26.7 g (0.05 mol) of 10, 11-bis- [2- (methylsulfonyloxy) ethyl] -2-bromo-dibenzofb, fiethiepin, 1.85 g (0.06 mol) of methylamine and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol the 7-bromo-3-methyl-2,3,4,5-tetrahydro-lH - dibenzo [2,3: 6,7] thiepino [4, 5-d] azepine, crude product; Hydrochloride mp 280 ° (with decomposition) (from absolute ethanol);

F) from 21.9 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] oxepine, 1.85 g (0.06 mol) of methylamine and 16.25 g (0.125 mol) diisopropylethylamine, the 3-methyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine, M.p. 147-149 ° (from acetonitrile); Hydrochloride mp 282-285 ° (from absolute ethanol);

I.

G) from 21.9 g (0.05 mol) of 10, 11-bis- [2- (methylsulfonyloxy) - ethyl] -dibenzo [b, f] oxepine, 3.5 g (0.06 mol) of isopropylamine and 16.25 g (0.125 mol) of diisopropylethylamine the 3-isopropyl-2,3,4,5-tetrahydro-lH-dibenzo [23: 6.7] oxepino [4,5-d] azepine, mp. 125 -128 ° (from acetonitrile); MaleatSmp. 175-177 ° (from acetone);

H) from 23.3 g (0.05 mol) of 10, 11-bis- [2- (methylsulfonyloxy) ethyl] -5-ethyl-5H-dibenzo [b, f] azepine, 1.85 g (0.006 Mol) methylamine and 16.25 g (0.125 mol) diisopropylethylamine the 3-methyl-10-ethyl-1,2,3,4,5,10-hexahydro-dibenzo [b, f] azepi-no [4, 5-d] azepine, mp 99-100 ° (from toluene); Oxalate mp 180 to 183 ° (from absolute ethanol);

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I) from 23.3 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -5-ethyl-5H-dibenzo [b, f] azepine, 3.4 g ( 0.06 mol) allyl-amine and 16.25 g (0.125 mol) diisopropyl-ethylamine the 3-A1-lyl-10-ethyl-l, 2,3,4,5,10-hexahydro-dibenzo [b, fjazepino [4,5 - djazepine, mp 100-101 ° (from hexane); Hydrochloride mp 245-248 ° (from absolute ethanol / acetone);

K) from 21.9 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxyethyl) -5H-dibenzo [b, f] azepine, 1.85 g (0.06 mol) Methylamine and 16.25 g (0.125 mol) diisopropylethylamine the 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo [b, f] azepino [4,5-d] azepine, mp . 121-124 ° (from methanol); methanesulfonate mp. 263 to 266 ° (from absolute ethanol / acetone); and

L) from 21.9 g (0.05 mol) of 10, ll-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenzo [b, f] azepine, 6.0 g (0.06 mol) (Aminomethyl-cyclopentane and 16.25 g (0.125 mol) diisopropylethylamine, the 3- (cyclopentylmethyl) -l, 2,3,4,5,10-hexahydro-di-benzo [b, f] azepine [ 4,5-d] azepine, mp 72-75 ° (from pentane); methanesulfonate mp 271-274 ° (from methanol).

The starting materials can be produced as follows: to B)

from 42.3 'g (0.1 mol) of 2-methoxy-10, l 1-bis- (bromomethyl) -di-benzo [b, f] thiepin and 11.8 g (0.24 mol) of sodium cyanide in 500 ml of acetonitrile the 2-methoxy-dibenzo [b, f] thiepin-10, l 1 - diacetonitrile, mp. 198-200 ° (from acetonitrile);

from 31.8 g (0.1 mol) of 2-methoxy-dibenzo [b, f] thiepin-10.11 - diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride the 2-methoxy-dibenzo [b , f] thiepin-10, l 1-di-acetic acid dimethyl ester, mp. 96-98 ° (from toluene);

from 38.5 g (0.1 mol) of 2-methoxy-dibenzo [b, f] thiepin-10, l 1 - dimethyl diacetate and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether 2-methoxy-dibenzo [b, f] thiepin-10, l 1-diethanol, mp. 116-119 ° (from ethyl acetate / hexane);

from 32.8 g (0.1 mol) of 2-methoxy-dibenzo [b, f] thiepin-10.11 - diethanol, 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine, the 10, ll -Bis- [2- (methylsulfonyloxy) ethyl] - 2-methoxy-dibenzo [b, f] thiepin, crude product;

to C)

from 44.2 g (0.1 mol) of 2-methylthio-10.1 l-bis- (bromomethyl) dibenzo [b, f] thiepin and 11.8 g (0.24 mol) of sodium cyanide in 500 ml of acetonitrile the 2-methylthio-dibenzo [b, f] thiepin-10, l 1-diacetonitrile, mp. 204-206 ° (from ethyl acetate);

from 33.4 g (0.1 mol) of 2-methylthio-dibenzo [b, f] thiepin - 10,11-diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride the 2-methylthio-dibenzo [b , f] -thiepin-10, ll-dimethyl diacetate, mp. 85-86 ° (from pentane);

from 40.0 g (0.1 mol) of 2-methylthio-dibenzo [b, f] thiepin - 10,11-diacetic acid methyl ester and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether, the 2nd -Me-thylthio-dibenzo [b, f] thiepin-10, l 1-diethanol, mp. 58-60 ° (from diethyl ether);

from 34.5 g (0.1 mol) of 2-methylthio-dibenzo [b, f] thiepin - 10,11-diethyl, 25.2 g (0.22 mol) of methanesulfonic acid chloride in

120 ml of pyridine, the 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-methylthio-dibenzo [b, f] thiepin, crude product;

to D)

from 41.0 g (0.1 mol) of 2-methyl-10, l l-bis- (bromomethyl) -di-benzo [b, f] thiepin and 11.8 g (0.24 mol) of sodium cyanide in 500 ml Acetonitrile the 2-methyl-dibenzo [b, f] thiepin-10, l 1-di-acetonitrile, mp. 198-200 ° (from acetonitrile);

from 30.2 g (0.1 mol) of 2-methyl-dibenzo [b, f] thiepin-10, l 1 - diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride the 2-methyl-dibenzo [ b, f] thiepin-10, ll-di-acetic acid dimethyl ester, mp. 76-77 ° (from methanol);

from 36.9 g (0.1 mol) of 2-methyl-dibenzo [b, f] thiepin-10, l 1-dimethyl diacetate and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether 2-methyl-dibenzo [b, f] thiepin-10,11-diethanol, mp 126-129 ° (from acetonitrile);

from 31.2 g (0.01 mol) of 2-methyl-dibenzo [b, f] thiepin-10, l 1 - diethanol, 25 2- g (0.22 mol) of methanesulfonyl chloride in 120 ml of pyridine the 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] - 2-methyl-dibenzo [b, f] thiepin, crude product;

zuE)

from 47.5 g (0.1 mol) of 2-bromo-10, l l-bis- (bromomethyl) -di-benzo [b, f] thiepin and 11.8 g (0.24 mol) of sodium cyanide in 500 ml Acetonitrile the 2-bromo-dibenzo [b, fJthiepin-10,11-di-acetonitrile, mp 200-204 ° (from acetonitrile);

from 36.7 g (0.1 mol) of 2-bromo-dibenzo [b, f] thiepin-10,11-di-acetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride the 2-bromo-dibenzo [ b, f] thiepin-10, l dimethyl 1-diesyl acetate, mp 90-93 ° from abs. Ethanol);

from 43.3 g (0.1 mol) of 2-bromo-dibenzo [b, f] thiepin-10, ll-di-acetic acid dimethyl ester and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether 2-bromo-di-benzo [b, f] thiepin-10,11-diethanol, mp 166-169 ° (from diethyl ether);

from 37.7 g (0.1 mol) of 2-bromo-dibenzo [b, f] thiepin-10,11-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine, the 10.1 l Bis- [2- (methylsulfonyloxy) ethyl] -2-bromo-dibenzo [b, f] thiepin, mp 94-96 ° (from benzene / ether);

from 27.2 g (0.1 mol) of naphtho [1,2-b] thiophene-4,5-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine, the 4,5- [2- (methylsulfonyloxy) ethyl] naphto [1,2-b] thiophen, mp 132-135 ° (from methylene chloride);

to F + G)

from 38 g (0.1 mol) of 10.1 l-bis (bromomethyl) dibenzo [b, f] oxepine and 11.8 g (0.24 mol) of sodium cyanide in 500 ml of acetonitrile the dibenzo [b, f ] oxepin-10, l 1-diacetonitrile, mp 176 to 178 ° (from methanol);

from 27.2 g (0.1 mol) of dibenzo [b, f) oxepin-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride, the dibenzo [b, f] oxepin-10, l 1 -diacetic acid dimethyl ester, mp. 65-67 ° (from pentane);

from 33.8 g (0.1 mol) of dibenzo [b, f] oxepin-10,11-diacetic acid - dimethyl ester and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether, the dibenzo [b, f ] oxepin - 10,11-diethanol, mp 138-140 ° (from acetone);

from 28.2 g of dibenzo [b, f] oxepin-10,11-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine, the 10, 11-bis- [2- (methylsulfonyloxy) ethyl ] -dibenzo [b, f] oxepine, mp 112-114 ° (from methylene chloride);

zuH + I)

from 42.1 g (0.1 mol) 5-acetyl-10, l l-bis- (bromomethyl) -5H - dibenzo [b, f] azepine and 11.8 g (0.24 mol) sodium cyanide in 500 ml of acetonitrile the 5-acetyl-5H-dibenzo [b, f] azepine-10, l 1 - diacetonitrile, mp. 183-185 ° (from benzene);

5-acetyl-5H from 31.3 g (0.1 mol) of 5-acetyl-5H-dibenzo [b, f] azepine-10.11 - diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride -dibenzo [b, f] azepine-10, l 1 - dimethyl acetate, mp 123-124 ° (from toluene);

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from 37.9 g (0.1 mol) of 5-acetyl-5H-dibenzo [b, f] azepine-10, l 1-dimethyl acetate and 7.6 g of lithium aluminum hydride in 150 ml of absolute tetrahydrofuran the 5-ethyl 5H-di-benzo [b, f] azepin-10, l 1-diethanol, mp. 102-105 ° (from ether);

from 30.9 g (0.1 mol) of 5-ethyl-5H-dibenzo [b, f] azepine-10.11 - diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine the 10, 1 l-bis- [2- (methylsulfonyloxy) ethyl] - 5-ethyl-5H-dibenzo [b, f] azepine, mp 140-143 ° (from toluene); to K + L)

5H-Dibenzo from 37.9 g (0.1 mol) of 5-acetyl-5H-dibenzo [b, f] azepine-10.11 - dimethyl acetate and 7.6 g of lithium aluminum hydride in 1 liter of absolute diethyl ether [b, f] azepine-10,11-diethanol, mp 180-182 ° (from acetone);

from 28.1 g (0.1 mol) of 5H-dibenzo [b, f] azepine-10,11-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine, the 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -5H-di-benzo [b, f) azepine, mp 140-142 ° (from toluene).

Example 7

A mixture of 18.6 g (0.05 mol) of 7-bromo-3-methyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, (prepared according to Example 6) 10.7 g (0.12 mol) of copper I-cyanide in 20 ml of dimethylformamide is heated to 180 ° in a nitrogen atmosphere with stirring for 22 hours. It is then cooled to 30 °, diluted with 100 ml of methylene chloride and mixed with 50 ml of a 50% aqueous ethylenediamine solution. The organic phase is then separated off, washed with water and evaporated after drying over sodium sulfate. The crystalline residue that melts 7-cyano-3-methyl-2,3,4,5-tetrahydro-1 H-dibenzo [2,3: 6,7] thiepino [4,5-d] aze-pin after recrystallization from hexane / ethyl acetate at 154-157 °.

For conversion into methanesulfonate, 9.6 g (0.03 mol) of base are dissolved in 50 ml of acetone, and 2.88 g (0.03 mol) of methanesulfonic acid are added to this solution while stirring, whereupon the 7-cyano-3-methyl- 2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thie-pino [4,5-d] azepine methanesulfonate of mp 247-250 ° crystallized out.

Example 8

To a solution of 16.9 g (0.05 mol) of 2,3,4,5-tetrahydro-1 H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-3- propanol in 50 ml of absolute pyridine, 12.2 g (0.075 mol) of octanoyl chloride are added dropwise with stirring, the temperature being kept between 0 and 5 °. The mixture is then left to stir at room temperature for 20 hours. The reaction mixture is poured onto ice water and extracted with ether. The organic phase is separated off, washed with water and, after drying over sodium sulfate, evaporated completely. The 3- (3-oc-tanoyloxypropyl) -2,3,4,5-tetrahydro-1 H-dibenzo [2,3: 6,7] thie-pino [4,5-d] azepine remains as an oily residue back.

21.5 g of crude base are dissolved in 150 ml of acetone and a solution of 4.2 g (0.047 mol) of anhydrous oxalic acid in 22 ml of absolute alcohol is added, whereupon the 3- (3-octanoyloxypropyl) -2,3,4 , 5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino- [4,5-d] azepine oxalate, which melts after recrystallization from absolute ethanol at 157-162 °. The following can be produced in an analogous manner:

from 16.9 g (0.05 mol) of 2,3,4,5-tetrahydro-lH-dibenzo [2,3: -6,7] thiepino [4,5-d] azepine-3-propanol in 50 ml absolute pyridine and 5.9 g (0.075 mol) of acetyl chloride, the 3- (3-acetoxypropyl) -2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5 -d] -azepine. The oxalate has a melting point of 156-160 ° (from absolute ethanol).

Example 9

75 ml of a 7.4% ethylamine solution in absolute ethanol (corresponding to 0.012 mol) are mixed with 3.25 g (0.025

Mol) diisopropylethylamine, 50 ml absolute ethanol and

4.5 g (0.01 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -di-benzo [b, f] thiepin (prepared according to Example 5) and heated in a closed tube for 20 hours at 85-90 °. After cooling, the reaction mixture is rinsed together with 250 ml of methylene chloride in a separating funnel and successively with 50 ml of 2-n. Sodium hydroxide solution and water shaken out. The methylene chloride solution is evaporated in a water jet vacuum and the crude 3-ethyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine is added to the hydrochloride as follows transferred: 3.1 g of residue, brown viscous oil, is dissolved in 25 ml of methylene chloride and with 3 ml of 4-n. ethereal hydrogen chloride solution. The 3-ethyl-2,3,4,5-tetrahydro-1 H-dibenzo [2,3: 6,7] thiepino- [4,5-d] azepine hydrochloride is precipitated with ether, filtered off with suction and once from ethanol / Ether recrystallized, mp. 271 ° (with decomposition), mp. Of methanesulfonate 212-214 °.

Example 10

Analogously to Example 9, the following compounds can be prepared using the corresponding starting materials:

3- methyl-1,5-dihydro-2H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-2,4 (3H) -dione, mp. 216-222 °,

2,3,4,5-tetrahydro-1 H-dibenzo [2,3: 6,7] thiepino [4,5-d] aze-pin, mp (after recrystallization from methanol) 142-143 °, mp. of methanesulfonate 305-307 °,

2,3,4,5-tetrahydro-lH-thien o [2 ', 3': 2,3] benzothiepino [4,5-djazepine, mp. 119-120 ° (from diethyl ether).

Example 11

8.38 g (0.03 mol) of 2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine are mixed with stirring in 6 ml of 85% Formic acid dissolved at 40-50 °. This solution is now mixed with 2.4 ml of 35% formaldehyde solution and then stirred for a further 12 hours at an internal temperature of 95-100 °. The reaction mixture is then cooled to 20 °, diluted with 100 ml of water and this solution is made up with conc. Ammonia-phenolphthalein-alkaline, the crude 3-methyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino- [4,5-d] azepine separating out as an oil. The crude base is extracted with ether, the organic phase is separated off, washed twice with water and, after drying over sodium sulfate, completely evaporated. The base is now converted into the methanesulfonate as follows:

8.4 g of crude base are dissolved in 40 ml of acetone and carefully mixed with 2.6 g of methanesulfonic acid, whereupon the 3-methyl-2,3,4,5-tetrahydro-lH-dibenzo [23: 6.7] thiepino [ 4,5-d] azepine - methanesulfonate crystallized, which melts after recrystallization from absolute ethanol at 256-258 °.

Example 12

8.38 g (0.03 mol) of 2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine are stirred in 80 ml of 50% dissolved acetic acid. 8.16 g (0.08 mol) of acetic anhydride are then added to this solution all at once and the mixture is left to stand at room temperature for 12 hours. The reaction mixture is then completely evaporated on a rotary evaporator, the residue is dissolved in ether, the ether solution once with hydrochloric acid and once with 2-n. Sodium hydroxide solution and washed twice with water. After drying over sodium sulfate, the ether solution is evaporated completely, the 3-acetyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5 - djazepine as a yellow oil remains. The 9.4 g of crude acetyl compound is dissolved in 150 ml of absolute diethyl ether and this solution is added dropwise to a suspension of within 1 hour

1.6 g (0.042 mol) of lithium aluminum hydride in 50 ml of absolute diethyl ether, the reaction mixture boiling

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is coming. The mixture is then refluxed for a further 6 hours. After cooling to 0-5 °, 40 ml of water are added dropwise to the reaction mixture and the organic phase is separated off; they are washed with water and, after drying over sodium sulfate, evaporated completely. The oily residue is dissolved in 10 ml of acetone and cooled to -10 °, whereupon the 3-ethyl-2,3,4,5-tetrahydro-lH-di-benzo [2,3: 6,7] thiepino [4, 5-d] azepine crystallized from mp. 106-107 °. The methanesulfonate is produced by the process according to Example 11, mp. 212-214 ° (from absolute ethanol).

Example 13

The following end product is produced analogously to Example 11:

from 14.3 g (0.05 mol) of 2,3,4,5-tetrahydro-lH-thieno [2 ', 3': - 2,3] [l] benzothiepino [4,5-d] azepine the 3rd -Methyl-2,3,4,5-tetra-hydro-lH-thieno [2 ', 3': 2,3] [l] benzothiepino [4,5-d] azepine as. Raw product; Methanesulfonate mp 208-209 ° (from absolute ethanol).

Example 14

The following end product is produced analogously to Example 12:

from 14.3 g (0.05 mol) of 2,3,4,5-tetrahydro-lH-thieno [2 ', 3': - 2,3] [l] benzothiepino [4,5-d] azepine the 3rd -AthyI-2,3,4,5-tetrahy-dro-lH-thieno [2 ', 3': 2,3] [l] benzothiepino [4,5-d] azepine, mp. 127-129 ° (from Acetone); Methanesulfonate mp 209-211 ° (from absolute ethanol).

Example 15

The following compounds can be prepared analogously to Example 9 using the appropriate starting materials:

3- [3- (dimethylamino) propyl] -2,3,4,5-tetrahydro-lH-di-benzo [2,3: 6,7] thiepino [4,5-d] azepine as crude product; Dihydrochloride mp 285-289 ° (with decomposition).

3- [3- (Dimethylamino) propyl] -2,3,4,5-tetrahydro-lH-thie-no [2 ', 3': 2,3] [l] benzothiepino [4,5-d] azepine as a raw product; Di-hydrochloride mp. 265-270 ° (with decomposition).

3- [3- (dimethylamino) propyl] -1,2,3,4,5,10-hexahydro-di-benzo [3,4: 6,7] cyclohepta [1,2-d] azepine, m.p. 80-82 ° (from pentane); Dihydrochloride mp. Approx. 315 ° (with decomposition).

Example 16

Analogously to Example 5, the following compounds can be prepared using the corresponding starting materials:

from 22.7 g (0.05 mol) of 10, ll-bis- [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] thiepin, 4.4 g (0.06 mol) of n-butylamine and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol the 3-butyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepi-no [4,5-d ] azepine, mp 107-108 ° (from acetone); Methanesulfonate mp 218-220 ° (from absolute ethanol);

from 22.7 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] thiepin, 3.4 g (0.06 mol) of allylamine and 16 , 25 g (0.125 mol) diisopropylethylamine in absolute ethanol the 3-allyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thie-pino [4,5-d] azepine as a raw product; Methanesulfonate mp 225 to 227 ° (from absolute ethanol);

from 22.7 g (0.05 mol) 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin, 3.3 g (0.06 mol) propargylamine and 16 , 25 g (0.125 mol) diisopropylethylamine in absolute ethanol the 3-propynyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: -6,7] thiepino [4,5-d] azepine as a raw product; Methanesulfonate mp 218-221 ° (from absolute ethanol);

from 22.7 g (0.05 mol) 10, 11-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin, 6.0 g (0.06 mol) (aminomethyl) - -cyclopentane and 16.25 g (0.125 mol) diisopropyl-ethylamine

624 105

in absolute ethanol the 3- (cyclopentylmethyl) -2,3,4,5-tetra-hydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, mp. 113 to 115 ° (from absolute ethanol); Methanesulfonate mp 248-252 ° (from absolute ethanol);

from 22.7 g (0.05 mol) 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] thiepin, 6.7 g (0.06 mol) (aminomethyl) --cyclohexane and 16.5 g (0.125 mol) diisopropylethylamine in absolute ethanol, the 3- (cyclohexylmethyl) -2,3,4,5-tetrahy-dro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, mp 113-115 ° (from acetone); Methanesulfonate mp 256-258 ° (from absolute ethanol);

from 22.7 g (0.05 mol) 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin, 3.7 g (0.06 mol) ethanolamine and 16 , 25 g (0.125 mol) diisopropylethylamine in absolute ethanol, the l, 2,4,5-tetrahydro-3H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-3-ethanol , Mp 157-159 ° (from acetone); Methanesulfonate mp 194-198 ° (from absolute ethanol);

from 22.7 g (0.05 mol) 10.1 l-bis- [2- (methylsulfonyloxy) - ethyI] -dibenzo [b, f] thiepin, 4.5 g (0.06 mol) 3-aminopropanol and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol, the 1,2,4,5-tetrahydro-3H-dibenzo [2,3: 6,7] thiepino- [4,5-d] azepine-3 -propanol, mp. 120-132 ° (from acetone); Methanesulfonate mp 181-183 ° (from absolute ethanol);

from 22.7 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin, 5.4 g (0.06 mol) of 3-methoxypropyl amine and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol the 3- (3-methoxypropyl) -2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine as a crude product; Methanesulfonate mp 213-216 ° (from absolute ethanol);

from 22.7 g (0.05 mol) 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin, 6.3 g (0.06 mol) 3- ( Methylthio) propylamine and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol the 3- [3- (methylthio) propyl] -2,3,4,5-tetra-hydro-lH-dibenzo [2 , 3: 6.7] thiepino [4,5-d] azepine as a crude product; Methanesulfonate mp 212-214 ° (from absolute ethanol);

from 22.7 g (0.05 mol) 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin, 5.5 g (0.06 mol) 2- ( Methylthio) ethylamine and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol the 3- [2- (methylthio) ethyl] -2,3,4,5-tetra-hydro-lH-dibenzo [2 , 3: 6.7] thiepino [4,5-d] azepine, mp 91-92 ° (from pentane); Methanesulfonate mp 218-220 ° (from absolute ethanol);

from 24.5 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -2-chlorodibenzo [b, f] thiepin, 1.85 g (0.06 mol ) Methylamine and 16.25 g (0.125 mol) diisopropylethylamine in methanol the 7-chloro-3-methyl-2,3,4,5-tetrahydro-lH-dibenzo- [2,3: 6,7] thiepino [ 4,5-d] azepine as a crude product; Hydrochloride mp 266-268 ° (from absolute ethanol);

from 24.5 g (0.05 mol) 10, 11-bis- [2- (methylsulfonyoxy) - ethyl] -2-chlorodibenzo [b, f] thiepin, 6.7 g (0.06 mol) (Amino-methyl) -cyclopentane and 16.25 g (0.125 mol) diisopropyl-ethylamine in absolute ethanol the 7-chloro-3- (cyclopentyl-methyl) -2,3,4,5-tetrahydro-lH-dibenzo [ 2.3: 6.7] thiepin [4,5-d] azepine, mp 123-126 ° (from acetone); Methanesulfonate mp 195-198 ° (from absolute ethanol).

The starting material for the two last-mentioned end products can be prepared analogously to Example 5:

from 43.1 g (0.1 mol) of 2-chloro-10, l l-bis- (bromomethyl) -di-benzo [b, f] thiepin and 11.8 g of sodium cyanide in 500 ml of acetonitrile the 2-chloro dibenzo [b, f] thiepin-10,11-diacetonitrile, mp 207-210 ° (from chloroform);

from 32.3 g (0.1 mol) of 2-chloro-dibenzo [b, f] thiepin-10,11 -diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride the 2-chloro-dibenzo [b, f] thiepin-10, l 1-di-acetic acid dimethyl ester, mp. 111-113 ° (from methanol);

from 38.9 g (0.1 mol) of 2-chloro-dibenzo [b, f] thiepin-10,11-di-acetic acid dimethyl ester and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether 2-chlorine

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-dibenzo [b, f] thiepin-10,11-diethanol, mp. 152-154 ° (from diethyl esyl acetate); and from 33.3 g (0.1 mol) of 2-chloro-dibenzo [b, f] thiepin-10,11-diethanol, 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine, the 10, 11- Bis- [2- (methyisulfonyloxy) ethyl] -2-chloro-dibenzo [b, f] thiepin, mp. 118-120 ° (from diethyl ether).

Example 17

To a solution of 21.9 g (0.05 mol) of 10, 11-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] oxepine in 250 ml of absolute ethanol is added 6 g (0 , 06 mol) aminomethyl-cyclopentane and 16.25 g (0.125 mol) diisopropylethylamine and the reaction mixture is refluxed for 18 hours. After cooling with an ice bath, crystals separate out, which are suction filtered and washed with a little isopropanol and pentane. The suction filter is 3- (cyclopentimethyl) -2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] oxepino- [4,5-d] azepine, mp 99-101 ° represents mp of methanesulfonate 280 ° with decomposition.

The following can be produced in an analogous manner:

from 21.9 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] oxepine, 4.5 g (0.06 mol) of 3-aminopropanol and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol, the 1,2,4,5-tetrahydro-3H-dibenzo [2,3: 6,7] oxepino- [4,5-d] azepine-3 -propanol, mp 59-61 ° (from pentane); Methane sulfonate mp 188-192 ° (from absolute ethanol).

Example 18

27.6 g (0.1 mol) of 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo- [b, f] azepino [4,5-d] azepine are mixed in a mixture of 130 ml of hexametapol and 130 ml of absolute toluene dissolved with stirring. A suspension of 7.8 g (0.2 mol) of sodium amide in 24 ml of absolute toluene is added dropwise to this solution in the course of 15 minutes, the temperature being kept at 18-20 ° by gentle cooling; at the same time, a dry stream of nitrogen is passed through the reaction solution to drive off the ammonia formed. After the dropping has ended, the mixture is stirred for a further 30 minutes and then a solution of 14.2 g (0.1 mol) of methyl iodide in 100 ml of absolute toluene is added dropwise over the course of 15 minutes, the temperature still being kept at 18-20 ° by ice cooling is held. The reaction mixture is then left to stir for a further 15 minutes and then slowly poured onto a mixture of 2 liters of water and 400 ml of toluene. The organic phase is separated off and the aqueous phase is extracted with toluene. The combined organic solutions are washed with water and, after drying over potassium carbonate, evaporated completely in vacuo. The crystallized residue, the 3,10-dimethyl-1,2,3,4,5,10-hexahydro-dibenzo [b, f] azepino- [4,5-d] azepine, is recrystallized from ethanol and melts at 197 -199 °; Methanesulfonate mp 231-233 ° (from absolute ethanol).

The starting material can be prepared in the following manner as in Example 6H:

from 42.1 g (0.1 mol) of 5-acetyI-10, ll-bis- (bromomethyl) -5H - dibenzo [b, f] azepine and 11.8 g (0.24 mol) of sodium cyanide in 500 ml Acetonitrile the 5-acetyl-5H-dibenzo [b, f] azepine-10,11 - diacetonitrile, mp. 183-185 ° (from benzene);

from 31.3 g (0.1 mol) of 5-acetyl-5H-dibenzo [b, f] azepine-10, l 1 - diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride of the 5-acetyl 5H-dibenzo [b, f] azepine-10.11 - dimethyl acetate, mp 123-124 ° (from toluene);

37-g (0.1 mol) of 5-acetyl-5H-dibenzo [b, f] azepine-10.11 - dimethyl acetate and 7.6 g of lithium aluminum hydride in 150 ml of absolute tetrahydrofuran gave 5-ethyl -5H - dibenzo [b, f] azepine-10,11-diethanol, mp 102-105 ° (from ether);

from 30.9 g (0.1 mol) of 5-ethyl-5H-dibenzo [b, f] azepin-10, l 1 - diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine the 10th , 1 l-bis- [2- (methylsulfonyloxy) ethyl] - 5-ethyI-5H-dibenzo [b, f] azepine, mp 140-143 ° (from toluene);

from 37.9 g (0.1 mol) of 5-acetyl-5H-dibenzojb, f) azepine-10, l 1 - dimethyl acetate and 7.6 g of lithium aluminum hydride in 1 liter of absolute diethyl ether, the 5H-dibenzo [b, f] -azepin-10,11-diethanol, mp 180-182 ° (from acetone);

from 28.1 g (0.1 mol) of 5H-dibenzo [b, f] azepine-10, 1 1-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine the 10, 11- Bis- [2- (methylsulfonyloxy) ethyl] -5H-di-benzo [b, f] azepine, mp 140-142 ° (from toluene);

from 21.9 g (0.05 mol) of 10.1 l-bis- [2- (methylisulfonyloxy) ethyl] -5H-dibenzo [b, f] azepine, 1.85 g (0.06 mol) of methylamine and 16.25 g (0.125 mol) diisopropylethylamine the 3-methyl-l, 2,3,4,5,10-hexahydro-dibenzo [b, f] azepino [4,5-d] azepine, mp. 121-124 ° (from methanol); Methanesulfonate mp 263 to 266 ° (from absolute ethanol / acetone).

Example 19

The following compounds can be prepared analogously to Example 6F using the corresponding starting materials:

from 23.6 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -2-chlorodibenzo [b, f] oxepine, 1.85 g (0.06 mol ) Methylamine and 16.25 g diisopropylethylamine in absolute ethanol the 7-chloro-3-methyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: -6,7] oxepino [4,5 -d] azepine, mp. 174-176 ° (from toluene), hydrochloride mp. 279-281 ° (from absolute ethanol).

The starting material, the 10.1 l-bis- [2- (methylsulfonyloxy) - ethyl] -2-chlorodibenzo [b, f] oxepine, can be prepared as follows in accordance with Example 6F:

a) from 20.7 g (0.05 mol) of 10.1 l-bis- (bromomethyl) -2-chloro-dibenzo [b, f] oxepine and 5.9 g (0.12 mol) of sodium cyanide in 250 ml acetonitrile the 2-chloro-dibenzo [b, f] oxepin-10, l 1-di-acetonitrile, mp 227-230 ° (from methanol);

b) 2-chloro-dibenzo from 15.3 g (0.05 mol) of 2-chloro-dibenzo [b, f] oxepin-10,11 - diacetonitrile, 200 ml of methanol, 1.9 ml of water and dry hydrogen chloride [b, f] oxepin-10, l dimethyl 1-diesyl acetate, crude product (oil);

c) from 18.7 g (0.05 mol) of 2-chloro-dibenzo [b, f] oxepin-10, l 1 - dimethyl acetate and 3.8 g (0.1 mol) of lithium aluminum hydride in 500 ml of diethyl ether the 2-chloro-dibenzo [b, f] -oxepin-10,11-diethanol, crude product (oil); and d) from 15.8 g (0.05 mol) of 2-chloro-dibenzo [b, fjoxepin-10, ll - ethanol 12.6 g (0.11 mol) of methanesulfonic acid chloride in

60 ml of pyridine, the 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] -2-chloro-dibenzo [b, f] oxepine, crude product (oil).

Example 20

Analogously to Examples 5 and 6E, the following compounds can be prepared using the corresponding starting materials:

A) from 22.7 g (0.05 mol) of 10.1 l-bis- [2- (methylsulfonyloxy) ethyl] dibenzo [b, f] thiepin, 3.3 g (0.06 mol) of propylamine and 16.25 g of diisopropylethylamine in absolute ethanol, the 3-propyl-2,3,4,5-tetrahydro-1 H-dibenzo [2,3: 6,7] thiepin [4,6-d] azepine, M.p. 128-130 ° (from acetone); Methanesulfonate mp 181 to 183 ° (from absolute ethanol);

B) from 26.7 g (0.05 mol) of 10, 11-bis- [2- (methylsulfonyloxy) ethyl] -2-bromo-dibenzo [b, f] thiepin, 6.0 g (0.06 Mol) (amino-methyl) -cyclopentane and 16.25 g (0.125 mol) diisopropyl-ethylamine the 7-bromo-3- (cyclopentylmethyl) -2,3,4,5-tetrahy-dro-1H-dibenzo [2 , 3: 6.7] thiepino [4,5-d] azepine, mp 120-123 ° (from ethanol);

C) from 26.7 g (0.05 mol) 10, 11-bis- [2- (methylsulfonyloxy) ethyl] -2-bromo-dibenzo [b, f] thiepin, 2.7 g (0.06 Mol) ethylamine and 16.25 g (0.125 mol) diisopropylethylamine the 7-bromo

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-3-ethyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, crude product.

Example 21

A mixture of 19.3 g (0.05 mol) of 7-bromo-3-ethyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5- d] azepine, 10.7 g (0.12 mol) of copper I-cyanide in 20 ml of dimethylformamide is heated in a nitrogen atmosphere to 180 ° for 22 hours with stirring. It is then cooled to 30 °, diluted with 100 ml of methylene chloride and mixed with 50 ml of a 50% aqueous ethylenediamine solution. The organic phase is then separated off, washed with water and, after drying, evaporated over sodium sulfate. The crystalline residue, the 7-cyano-3-ethyl-2,3,4,5-tetrahydro-IH-di-benzo [2,3: 6,7] thiepino [4,5-d] azepine, melts after recrystallization from hexane / ethyl acetate at 154-156 °.

For conversion into methanesulfonate, 10 g (0.03 mol) of base are dissolved in 50 ml of acetone, and 2.88 g (0.03 mol) of methanesulfonic acid are added to this solution while stirring, whereupon the 7-cyano-3-ethyl-2, 3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thie-pino [4,5-d] azepine methanesulfonate of mp 220-223 ° crystallized out.

The following can be produced in an analogous manner:

from 22 g (0.05 mol) of 7-bromo-3- (cyclopentylmethyl) -2,3,4,6 - tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, 10.7g (0.12 mol) copper-I-cyanide in 20 ml dimethylformamide

7-cyano-3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-lH-diben-zo [2,3: 6,7] thiepino [4,5-d] azepine, mp 170-172 ° (from methanol); Methanesulfonate mp 203-206 ° (from absolute ethanol).

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Example 22

a) 15 g (0.05 mol) of dibenzo [b, f] thiepin-10,11-diethanol are dissolved in 200 ml of chloroform with stirring. A solution of 13.5 g (0.05 mol) of phosphorus tribromide in 100 ml of chloroform is added dropwise to this solution over 30 minutes while cooling with ice at a reaction temperature of 5-10 °. The reaction mixture is stirred for a further 15 hours at room temperature, then poured onto ice and the organic phase is separated off. The organic phase is washed with water, dried over sodium sulfate and evaporated. The residue, the 10.1 l-bis- [2- (bromo) ethyl] -dibenzo [b, f] thiepin, remains as a crude product.

b) 21.2 g (0.05 mol) of the crude product obtained under a) are mixed with a solution of 15.5 g (0.5 mol) of methylamine

2o stirred in 150 ml of absolute ethanol for 5 hours at a temperature of 65-70 °. The reaction mixture is then evaporated in vacuo and 100 ml of water are added to the residue, whereupon the 3-methyl-2,3,4,5-tetrahydro-lH-diben-zo [2,3: 6,7] thiepino [4, 5-d] azepine crystallized, which melts after drying and recrystallization from petroleum ether at 83 to 86 °.

Claims (6)

624 105 2nd 3. The method according to claim 1, characterized in that 1. A process for the preparation of new azatetracycles which comprises obtaining a compound of the formula I in which Rx is hydrogen by reaction with corresponding Al- R, converts dehydes or ketones under reducing conditions to ^ 5 compounds of the formula I, in which Rx 1 saying 1 has the meaning given with the exception of water N k serstoff. 4. The method according to claim 1, characterized in | ^ that a compound of formula I obtained, wherein Rj \ / io represents a hydroxy lower alkyl group by means of acylation in / m = * \ / ^ \ (!) represents a phenyl-lower alkyl group by hydrogenolysis • • • • kanoyloxy lower alkyl group means i »• • 5. Process according to claim 1, characterized in that \ X XZ7 that a compound of the formula I obtained, in which Rj i5 is a phenyl-lower alkyl group, is converted by hydogenolysis into a compound of the formula I in which Rj is R! Is hydrogen, lower alkyl, cycloalkyl-lower alkyl with up to serstoff. 10 carbon atoms, lower alkenyl, lower alkynyl, di-lower 6. The method according to claim 1, characterized in alkylamino-lower alkyl, free, etherified or esterified hy- that one obtained a compound of formula I, wherein R3 doxy-lower alkyl, etherified mercapto lower alkyl, or counter 20 Represents hydrogen, by reaction with a reaction-optionally substituted phenyl-lower alkyl, a capable lower alkyl ester converting into a compound of the formula I-optionally present heteroatom by at least 2, in which R 3 is lower alkyl. Carbon atoms is separated from the ring nitrogen atom, and the 7th method according to claim 1, characterized in that ring A is unsubstituted or halogen to atom number 35, that a compound of formula I obtained, wherein R3 is lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl 25 is hydrogen, first acylated, and then the formed or cyan substituted carbonyl group reduced by a compound of formula I. X to obtain oxygen, sulfur, methylene or a divalent, in which R3 represents lower alkyl. The rest of sub-formula 8. The method according to claim 1, characterized in that ^ y that a mixture of isomers obtained is broken down into the isomers. N 30 separates. I (Ia) 9. The method according to claim 1, characterized in r3 that compounds of the formula I are prepared in which Rx is hydrogen, lower alkyl, cycloalkyl-lower alkyl having up to 10 Koh-, in which R3 is hydrogen or lower alkyl, and lenstoffatomen, lower alkenyl, lower alkynyl, di-lower alkyl-one of the radicals Y and Z vinylene or Sulfur and the other 35 amino-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower means a direct bond, characterized in that alkyl, alkanoyloxy-lower alkyl, lower alkylthio-lower alkyl means a reactive diester of a diethanoi or phenyl-lower alkyl, and the ring A is unsubstituted Formula or by halogen to atom number 35, lower alkyl, Niederalkoxy, Niederalkylthio, Trifluormethyl or Cyan mo-HO-CH ^ CH2 40 nosubstituted, X is oxygen, sulfur, methylene or the £ y £ divalent rest of sub-formula Ia . Y ai) \ / ^ \ \ N î A M! ì * «I (la) • V ^ x'V means, in which R3 represents hydrogen or lower alkyl, and with a compound of the formula one of the radicals Y and Z vinylene or sulfur and the other means a direct bond. Rj 10. The method according to claim 1, characterized in j that compounds of the formula I are prepared in which Ri was N (III) serstoff, lower alkyl, cycloalkyl-lower alkyl with 4- 8 carbon X \ atoms, lower alkenyl, lower alkynyl, di-lower alkyl H H 55 amino lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylthio-lower alkyl or phenyl-lower alkyl, and if desired indicates an available free compound, ring A unsubstituted or halogenated to salt and / or, if desired, an atom number 35, lower alkyl, lower alkoxy, lower alkylthio, liches Salt is substituted in the free compound or in another salt trifluoromethyl or cyan, X oxygen, sulfur transferred. so fei, methylene or the divalent radical of sub-formula Ia 2. The method according to claim 1, characterized in - means that a compound of formula I obtained, wherein Rx Represents hydrogen by reaction with a reaction \ / capable ester of a corresponding alcohol of formula N RjIV - OH, wherein RXIV is the 65 I (Ia) given for Rj in claim 1 With the exception of hydrogen, it is important for a R3 Conversion of formula I, wherein Rx that in claim 1 has the meaning given with the exception of hydrogen. in which R3 represents hydrogen or lower alkyl and one 624 105 the radicals Y and Z are vinylene or sulfur and the other is a direct bond. 11. The method according to claim 1, characterized in that compounds of the formula I are prepared in which Rx is hydrogen, lower alkyl, cycloalkyl-lower alkyl having 4-8 carbon atoms, lower alkenyl, lower alkynyl, di-lower alkyl-amino lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylthione lower alkyl or phenyl-lower alkyl, ring A is unsubstituted or substituted by chlorine, X is sulfur or methylene and Y is a direct bond and Z is vinylene or sulfur. 12. The method according to claim 1, characterized in that compounds of the formula I are prepared in which Rt is hydrogen or lower alkyl and the ring A is unsubstituted, X is sulfur or methylene and Y is a direct bond and Z is vinylene or sulfur. 13. The method according to claim 1, characterized in that 3-methyl-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thie-pino [4,5-a] azepine is prepared .